Targeting Prostate Cancer Lineage Plasticity with BET Bromodomain Inhibition

通过 BET Bromodomain 抑制来靶向前列腺癌谱系可塑性

基本信息

批准号：
10026750
负责人：
Joshi James Alumkal
金额：
$ 39.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10026750
关键词：
ATAC-seq Androgen Receptor Bromodomain Cancer Patient Castration Cell Survival ChIP-seq Chromatin Clinical Trials Dependence Disease Progression Drug resistance E2F transcription factors Gene Expression Genes Genetic Transcription Goals Histology Histone Acetylation Histone H3 Implant In Vitro Lead Lysine Malignant neoplasm of prostate Measures Modeling Mus Neurosecretory Systems Nucleic Acid Regulatory Sequences Organoids Patients Pharmacology Phenotype Program Sustainability Prostate Prostate Adenocarcinoma Proteins Reader Receptor Signaling Sampling Signal Pathway Systems Biology Testing Time Transcriptional Activation Virulent Xenograft procedure abiraterone activating transcription factor design effective therapy high risk histone acetyltransferase inhibitor/antagonist loss of function men outcome prediction phase I trial predictive marker prevent programs prostate cancer cell prostate cancer cell line receptor function resistance mechanism response response biomarker transcription factor transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

Lineage plasticity in prostate cancer cells—defined as loss of androgen receptor (AR) signaling and switch from a luminal to an alternate differentiation program—is now recognized as a critical determinant of lethality in prostate cancer. The most virulent form is neuroendocrine prostate cancer (NEPC). De novo NEPC is rare (<1% of patients). However, we recently found that castration-induced, treatment-emergent (t-NEPC) is much more frequently found in tumors from men resistant to drugs such as abiraterone or enzalutamide. This strongly suggests AR interference promotes the emergence of this phenotype. There are no effective therapies for t-NEPC, and t-NEPC patients are often excluded from clinical trials due to t-NEPC’s aggressiveness. Thus, there is a clear need to develop new treatments. Recently, we discovered that specific transcription factors (TFs) and the BET bromodomain protein BRD4 cooperate to promote t-NEPC differentiation and cell survival. This application is designed to clarify mechanisms by which these TF and BRD4 function and to block those mechanisms. Our long term goal is to develop pharmacological strategies that prevent the emergence of lethal t-NEPC. Towards that goal, we determined that targeting BET bromodomain proteins with BET inhibitors (BETi) or BET PROTAC degraders (BETd) is a promising approach to block the lineage switch to t-NEPC and to block t-NEPC cell survival in vitro. The studies we describe herein are designed to test the hypotheses that BRD4 and cooperating TFs activate a lineage plasticity program that sustains survival of t-NEPC cells; targeting this BRD4/TF axis is a rational approach to prevent or delay t-NEPC disease progression. Aim 1: Determine mechanisms by which BRD4 cooperates with specific TFs to promote expression of a t-NEPC lineage plasticity survival program. Completion of this aim will provide a detailed understanding of how BRD4 and cooperating factors promote lineage plasticity and will determine whether activation of these TFs is reliable predictive marker of favorable BET inhibitor response. Aim 2: Treat t-NEPC patient tumors implanted in mice with BETi or BETd and measure anti-tumor activity and NEPC differentiation. Completion of this aim will provide the rationale for BETi or BETd clinical trials in t-NEPC patients and identify adaptive resistance mechanisms. Aim 3: Prevent castration-induced t-NEPC lineage switch with BETi or BETd using a patient tumor model of t-NEPC lineage switch implanted in mice. Completion of this aim will provide the rationale to test BETi or BETd in patients at high-risk for t-NEPC conversion and identify biomarkers of response. We expect that the studies proposed will clarify mechanistically the function of transcriptional network that is critical for the emergence and survival of t-NEPC. These results will help identify new approches to block this network in men with t-NEPC in the near-term.

前列腺癌细胞的谱系可塑性——定义为雄激素受体 (AR) 信号传导和转换的丧失从管腔分化程序到替代分化程序——现在被认为是致命性的关键决定因素前列腺癌的毒性最强的是神经内分泌前列腺癌（NEPC），这种癌症很罕见。（<1% 的患者）然而，我们最近发现去势引起的治疗紧急 (t-NEPC) 较多。更常见于对阿比特龙或恩杂鲁胺等药物耐药的男性肿瘤。强烈表明 AR 干扰促进了这种表型的出现。目前尚无有效的治疗方法。对于 t-NEPC，由于 t-NEPC 的侵袭性，t-NEPC 患者经常被排除在临床试验之外。显然需要开发新的治疗方法。最近，我们发现特定的转录因子（TF）和 BET 溴结构域蛋白 BRD4 合作促进 t-NEPC 分化和细胞存活。本申请旨在阐明。这些 TF 和 BRD4 发挥作用的机制以及阻断这些机制是我们的长期目标。为了实现这一目标，我们制定了防止致命 t-NEPC 出现的药理学策略。确定用 BET 抑制剂 (BETi) 或 BET PROTAC 降解剂靶向 BET 溴结构域蛋白 (BETd) 是一种有前景的方法，可阻断向 t-NEPC 的谱系转换并阻断 t-NEPC 细胞在体外的存活。我们在此描述的研究旨在测试 BRD4 和协同 TF 激活的假设维持 t-NEPC 细胞存活的谱系可塑性计划是合理的；预防或延缓 t-NEPC 疾病进展的方法。目标 1：确定 BRD4 与特定 TF 合作促进表达的机制 t-NEPC 谱系可塑性生存计划的完成将提供对 t-NEPC 谱系可塑性生存计划的详细了解。 BRD4 和协同因子如何促进谱系可塑性，并将决定这些因子的激活是否有效 TF 是有利的 BET 抑制剂反应的可靠预测标志。目标 2：用 BETi 或 BETd 治疗植入小鼠体内的 t-NEPC 患者肿瘤并测量抗肿瘤效果活性和 NEPC 分化的完成将为 BETi 或 BETd 临床提供依据。在 t-NEPC 患者中进行试验并确定适应性耐药机制。目标 3：使用患者肿瘤使用 BETi 或 BETd 预防去势诱导的 t-NEPC 谱系转换植入小鼠体内的 t-NEPC 谱系开关模型的完成将为测试提供依据。 t-NEPC 转化高风险患者的 BETi 或 BETd 和生物标志物反应识别。我们期望所提出的研究将机械地阐明转录网络的功能对于 t-NEPC 的出现和生存至关重要，这些结果将有助于确定阻止这种情况的新方法。近期在患有 t-NEPC 的男性中建立网络。